Project Summary Over the past half century there have been hundreds, if not thousands, of studies identifying cardioprotective agents, but relatively few have progressed to the clinics. There are probably several reasons for this lack of translational success: 1. That models identifying these potential cardioprotective mechanisms are based on acute experiments, not similar to chronic ischemia in patients; 2. many prior protective mechanisms cannot induce angiogenesis/arteriogenesis, which is required for patients with chronic myocardial ischemia and limited coronary blood flow; and 3. the data were derived solely from rodent models. The current application is based on the discovery of a novel cardioprotective agent, sFRP3, which was found in pigs with chronic preconditioning. Although relatively little is known about this gene in heart disease, it has been also found to be upregulated in patients with heart disease, which stimulated prior studies to conclude that sFRP3 exerted an adverse effect in heart failure, a conclusion diametrically opposed to our hypothesis and preliminary data. One of the major limitations to clinical translation of prior cardioprotective agents, is the inability to improve myocardial blood flow to the chronically ischemic heart by inducing angiogenesis/arteriogenesis. Our preliminary data indicate that sFRP3 induces both angiogenesis and arteriogenesis, which makes it an important new mechanism designed for not only acute cardioprotection, but also protects against chronic myocardial ischemic disease and finally will be of use to protect other organs where compromised blood flow induces disease, e.g., peripheral arterial and cerebral vascular disease. We will study 2 major hypotheses: Hypothesis A: sFRP3, when overexpressed either by injection into the heart, or genetically, exerts an important protective effect on coronary vessels, by induction of angiogenesis/arteriogenesis. Hypothesis B: sFRP3 induced protection against acute coronary artery occlusion is mediated by novel signaling mechanisms rather than angiogenesis/arteriogenesis.